As of 2005, 21 million people in the US have diabetes mellitus. Of those 21 million people, approximately 5- 10% have been diagnosed with type 1 diabetes. Type 1 diabetes results from the auto-immune mediated destruction of pancreatic [unreadable] cells. Since these cells are the only cells in the body that produce insulin, patients with type 1 diabetes are dependent upon exogenous insulin administration for survival. Alternative treatment modalities involving cadaveric pancreas or islet transplants possess several limitations such as tissue availability, high cost, and toxicity of necessary immunosuppressive medications, and are associated with variable results due to ongoing auto-immune attack by T cells. Thus attempts at developing alternative therapies for type 1 diabetes must focus-not only on regeneration, but also at abating the auto-immune destruction of the newly regenerated [unreadable] cells. Our lab in collaboration with Dr. Jerry Nadler, has demonstrated that treatment of diabetic mice with a combination of the novel anti-inflammatory agent, lisofylline (LSF), and the FDA approved [unreadable] cell growth factor, exendin-4 (Ex-4), results in the reversal of the diabetic phenotype and in the neogenesis of insulin positive cells within the pancreas. The overall goal of this project is to determine the cellular origin of these insulin positive cells, and to characterize the metabolic phenotype resulting from combined therapy. I hypothesize that the apparent reversal of the diabetic phenotype observed during combined LSF/Ex-4 treatment is a consequence of islet regeneration that may result from either proliferation of existing islet cells or transdifferentiation of resident ductal cells within the pancreas. Successful completion of this project will lead to an understanding of the cellular mechanisms of this combined therapy, and lay the foundation for their potential mechanisms in humans. To achieve our goals we propose the following specific aims: (Aim 1) Identify cellular lineage of insulin producing cells generated in response to combined LSF/Ex-4 therapy: This aim will be accomplished in two parts. First we will characterize the temporal and spatial expression of various pancreatic and proliferative markers using immunohistochemistry and RT-PCR. Next, we will perform direct lineage tracing using a transgenic mouse model in which a tamoxifen inducible Cre transgene is driven by a pancreatic endocrine specific promoter pdx1PB. (Aim 2) Assess Beta cell function and metabolism in mice treated with combined therapy: This aim will be accomplished by determining the responsiveness of [unreadable] cells to glucose, the insulin sensitivity of peripheral tissues, and the level of glucose stimulated insulin secretion.